Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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METHODS AND COMPOSITIONS USING TERFENADINE METABOLITES
IN COMBINATION WITH LEUXOTRIENE INHIBITORS
1. FIELD OF THE INVENTION
The invention relates to methods of treating
asthma, allergic conditions, and inflammation. In another
aspect, this invention relates to the use of antihistamines
and leukotriene inhibitors,-and to compositions containing
them.
.1:0
3. BACKGROUND OF THE INVENTION
Terfenadine is an antagonist of the H-1 histamine
receptor protein, which mediates the response antagonized by
conventional antihistamines. Terfenadine is well absorbed
but is extensively metabolized. See Okerhoim et al.,
Biopharmaceutics and Drug Distribution, 2: 185-190 (1981).
Two main metabolites have been identified and one of the
metabolites, fexofenadine, chemically named 4-[l-hydroxy-4-
[4-(hydroxydiphenylmethyl-l-piperidinyl)butyl]-a,a-
Z0 dimethylbenzeneacetic acid, is reported to have
antihistaminic activity. See Gartiez et al., Arzneimittel
Forschung/Drug-Research; 32: 1185-1190 (1982).
Recently, the FDA has approved the use of
fexofenadine as a prescription antihistamine (ALLEGRA ) for
,25 allergic rhinitis. Fexofenadine is said to have the
beneficial effects of terfenadine while having a reduced risk
of cardiotoxicity. See, e.g., U.S. Patent No. 5,375,683.
It has been suggested that the moderate
effectiveness of some Hl-antihistamines are due to their
30 additional activity against leukotrienes, particularly LTD,.
In one study of guinea pigs, the increase in airway
resistance caused by LTD, (leukotriene D,) was suppressed by
terfenadine. See Akagi et al., Oyo Yakuri, 35: 361-371
(1988). Another study was conducted that investigated the
35 development of dual antagonists of H1- and LTD,- receptors.
Twenty (20) H1-antihistamines with diverse chemical structures
were tested for activity against LTD,-induced contraction in
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isolated guinea-pig ileum and displacement of [3H] LTD, from
guinea-pig lung membrane proteins [M. Zhang et al., Inflamm.
res. 46:Supp. I S93-S94 (1997)]. The results indicated the
drugs were weakly active in inhibiting LTD4-induced
contraction of guinea pig ileum. The study further mentioned
a possible mechanism for loratadine and terfenadine, but
concluded that the mechanism does not appear to warrant great
attention for drug development.
Similarly, F. Baroody et al. report that
terfenadine treatment partially inhibits the early nasal
response to allergen challenge and subsequent reactivity to a
challenge with methacholine without affecting the influx of
eosinophils into nasal secretions. Treatment tended to
decrease levels of tryptase, prostaglandin D2 and leukotriene
Cõ but the differences did not achieve statistical
significance relative to the placebo [F.. Baroody et al.,
Arch. Otolaryngol. Head Neck Surg., 122:309-316 (Mar. 1996)].
Compounds within the class of non-sedating
antihistamines have been known to cause severe adverse
:20 electrophysiologic side-effects when administered to a human."
These adverse side-effects are associated with a prolonged QT
interval and include, but are not limited to, ventricular
fibrillation and cardiac arrhythmias, such as ventricular
tachyarrhythmias or torsades de pointes. Quercia et al.,
Z5 Hosp. Formul. 28: 137, 142 (1993); Knowles, Canadian Journal
Hosp. Pharm., 45: 33,37 (1992); Craft, British Medical
Journal, 292: 660 (1986); Simons et al., Lancet, 2: 624
(1988); and Unknown, Side Effects of Drugs Annual, 12: 142
and 14: 135. More recently, clinical practitioners have
.=30 noted an increase in the occurrence of these cardiac
arrhythmias upon co-administration of terfenadine with other
drugs such as ketoconazole and erythromycin or upon overdose
of terfenadine. Quercia et al., Hosp. Formul. 28: 137, 142
(1993).
=.35 Leukotrienes augment neutrophil and eosinophil
migration, neutrophil and monocyte aggregation, leukocyte
adhesion, increase capillary permeability, and smooth muscle
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contraction, all of which contribute to inflammation, edema,
mucus secretion, and bronchoconstriction. For example,
zileuton, commercially available as ZYFLO , is a specific
inhibitor of 5-lipoxygenase and has the chemical name ( )-1-
(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known
to inhibit leukotriene (LTH,, LTCõ LTDõ and LTE,) formation
in vitro. Zileuton is an inhibitor ex vivo of LTB, formation
in several species and inhibits leukotriene-dependent smooth
muscle contractions in vitro in guinea pig and human airways.
One study of 373 patients indicated that 600 mg of zileuton
four times daily were required to provide efficacy, while 400
mg failed to do so. In some patients, zileuton was reported
to cause headache, pain, asthenia, dyspepsia, nausea, and
myalgia. [Physician's Desk Reference, 52 ed., Medical
Economics Co., Inc., 474-76 (1998)].
Zafirlukast, sold commercially as ACCOLATE , is
another type of leukotriene inhibitor. This leukotriene
inhibitor is a leukotriene receptor antagonist (LTRA) of
leukotriene D, and E4, and has the chemical name 4-(5-
cyclopentyloxy-carbonylamino-l-methyl-indol-8-ylmethyl)-3-
methoxy-N-o-tolylsulfonylbenzamide. Cysteinyl leukotriene
production and receptor occupation have been correlated with
the pathophysiology of asthma. In vitro studies indicated
that zafirlukast antagonized the contractile activity of
three leukotrienes in conducting airway smooth muscle from
laboratory animals and humans; prevented intradermal LTD,-
induced increases in cutaneous vascular permeability; and
inhibited inhaled LTD,-induced influx of eosinophils into
animal lungs. In some patients, zafirlukast has been
reported to cause headache, infection, nausea, diarrhea,
pain, asthenia, abdominal pain, dizziness, myalgia, fever,
vomiting, SGPT elevation, and dyspepsia. [Physician's Desk
Reference, 52 ed., Medical Economics Co., Inc., 3148-49
(1998)].
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:3. SUMMARY OF THE INVENTION
The present invention represents an improvement
over terfenadine and the terfenadine metabolites, as well as
the leukotriene inhibitor, technology presently available.
=5 This invention relates to novel pharmaceutical
compositions comprising: (a) a metabolite of terfenadine;
(b) a leukotriene inhibitor; and optionally (c) a
decongestant; and a pharmaceutically acceptable carrier or
excipient. A "metabolite of terfenadine" or a "terfenadine
metabolite," as defined herein, includes 4-[1-hydroxy-4-(4-
hydroxydiphenylmethyl-l-piperidinyl)butyl]-a,a-
dimethylbenzeneacetates, 4-[l-hydroxy-4-(4-
hydroxydiphenylmethyl-i-piperidinyl)butyl-a,a-
dimethylbenzeneacetic acid (fexofenadine), and 1-[p-(2-
hydroxymethyl-2-propyl)phenyl)-4-[4-(a-hydroxy-a-
phenylbenzyl)-i-piperidinyl]butanol, or an optically pure
stereoisomer of any of the above compounds, or a
pharmaceutically acceptable salt of any of the above
compounds or stereoisomers (See, e.g., U.S. Patent No.
:20.5,375,683).
The compositions of the invention employing a
terfenadine metabolite and a leukotriene inhibitor, and
optionally a decongestant, possess potent antihistaminic
activity and are useful in treating, preventing, or managing
.-25 asthma, asthma symptoms, allergic rhinitis, inflammation, and
other allergic disorders, as well as dermatitis. The
compositions employing a terfenadine metabolite and a
leukotriene inhibitor are preferred, and these provide an
improvement in overall therapy relative to terfenadine or a
.30 terfenadine metabolite alone. In addition, the compositions
of the invention reduce or avoid adverse effects associated
with administration of other non-sedating antihistamines or
derivatives thereof, such as terfenadine, including, but not
limited to, cardiac arrhythmias, drowsiness, nausea, fatigue,
:35 weakness and headache. The compositions of a terfenadine
metabolite and a leukotriene inhibitor are also useful in
combination with non-steroidal anti-inflammatory agents or
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other non-narcotic analgesics for the treatment or prevention
of cough, cold, cold-like, and/or flu symptoms and the
discomfort, headache, pain, fever, and general malaise
associated therewith. The aforementioned combinations (e.g.,
a terfenadine metabolite and a leukotriene inhibitor) may
optionally include one or more other active components
including a decongestant, cough suppressant/antitussive, or
expectorant.
Additionally, the novel pharmaceutical compositions
.10 of the invention are useful in treating, preventing, or
managing motion sickness, vertigo, diabetic retinopathy,
small vessel complications due to diabetes and such other
conditions as may be related to the activity of these
derivatives as antagonists of the H-1 histamine receptor.
The compositions can be used to treat or prevent these
disorders while reducing or avoiding adverse effects
associated with administration of other non-sedating
antihistamines including a-aryl-4-substituted
piperidinoalkanol derivatives, such as terfenadine.
-20 In one embodiment, this invention provides for a
method of preventing or treating asthma or asthma symptoms in
a human which comprises administering to a human a
therapeutically effective amount of a terfenadine metabolite
and a therapeutically effective amount of a leukotriene
.25 inhibitor.
The invention also provides a method of preventing
or treating asthma or asthma symptoms in a human, comprising
administering to a human a composition, said composition
comprising (i) a therapeutically effective amount of a
30 terfenadine metabolite or a pharmaceutically acceptable salt
thereof; (ii) a leukotriene inhibitor selected from the group
consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase
activating protein antagonists, and leukotriene receptor
antagonists; (iii) optionally a therapeutically effective
35 amount of a decongestant; and a pharmaceutically acceptable
carrier or excipient.
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This invention is further directed to a method of
preventing or treating asthma or the symptoms of asthma in a
human which comprises administering to a human
therapeutically effective amounts of a terfenadine
.5 metabolite, a leukotriene inhibitor, and a decongestant.
In a second embodiment, the invention also provides
.for a method of preventing or treating allergic rhinitis in a
human which comprises administering to a human a
therapeutically effective amount of a terfenadine metabolite,
or a pharmaceutically acceptable salt thereof, a leukotriene
inhibitor, and optionally a decongestant, such that all three
active ingredients are used.
In a third embodiment, the invention provides for a
method of preventing or treating dermatitis in a human which
35 comprises administering to a human a therapeutically
effective amount of a terfenadine metabolite or a
pharmaceutically acceptable salt thereof, a leukotriene
inhibitor, and optionally a decongestant, such that all three
active ingredients are used.
:2`0 In a fourth embodiment, the invention provides for
a method of preventing or treating inflammation in a human
which comprises administering to a human a therapeutically
effective amount of a terfenadine metabolite or a
pharmaceutically acceptable salt thereof, a leukotriene
25 inhibitor, and optionally a decongestant, such that all three
-active ingredients are used.
In a fifth embodiment, the invention provides for a
-method of preventing or treating a condition responsive to
leuktotriene inhibition in a human which comprises
.0 administering to a human a therapeutically effective amount
of a terfenadine metabolite or a pharmaceutically acceptable
salt thereof, a leukotriene inhibitor, and optionally a
decongestant, such that all three active ingredients are
used.
5 It should be recognized that the compositions and
methods include the use of optically pure stereoisomers of
the terfenadine metabolites, as well as pharmaceutically
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acceptable salts of the stereoisomers. Thus, the invention
includes the (R)- and (S)- enantiomer, and the racemic
mixture, or a pharmaceutically acceptable salt thereof, of
each terfenadine metabolite. The methods and compositions
.5 preferably employ racemic fexofenadine, or optically pure
(R)-fexofenadine or (S)-fexofenadine, or pharmaceutically
acceptable salts thereof, more preferably (R)-fexofenadine
substantially free of (S)-fexofenadine or (S)-fexofenadine
substantially free of (R)-fexofenadine, or pharmaceutically
:10 acceptable salts thereof.
The invention encompasses the treatment,
prevention, and/or management of asthma, the symptoms of
asthma, dermatitis, allergic rhinitis, or inflammation using
a metabolite of terfenadine, preferably fexofenadine, and a
.15 leukotriene inhibitor. The invention also encompasses the
treatment, prevention, and/or management of these disorders
with a terfenadine metabolite, a leukotriene inhibitor, and
optionally a decongestant. The invention encompasses the
treatment, prevention, and/or management of these disorders
.:20 using a single unit dosage form that contains a terfenadine
metabolite, a leukotriene inhibitor and optionally a
decongestant, such that a terfenadine metabolite and a
leukotriene inhibitor or all three active ingredients are
used. However, it should be recognized that combination
:25 therapy by separate administration of each active ingredient
is also contemplated. The methods and compositions of this
invention are believed to reduce or avoid adverse effects
associated with the administration of non-sedating
antihistamines, such as terfenadine. The methods and
30 compositions described herein are believed to provide
superior or improved therapy over prior art methods and
compositions involving a terfenadine metabolite in the
absence of a leukotriene inhibitor, or a leukotriene
inhibitor in the absence of a terfenadine metabolite.
:35 Without being limited by theory, it is believed that the
combination of a terfenadine metabolite, a leukotriene
inhibitor, and optionally a decongestant, provides superior,
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improved, and synergistic effects unachievable by any of
these compounds alone.
-4. DETAILED DESCRIPTION OF THE INVENTION
The administration of a terfenadine metabolite, a
leukotriene inhibitor, and optionally a decongestant, in the
methods of the present invention may be either concurrently
or sequentially, i.e., a terfenadine metabolite, .a
leukotriene inhibitor, and the optional decongestant may be
administered as a combination (a single unit dosage) or
concurrently but separately. They may also be provided by
the sequential administration of a terfenadine metabolite,
leukotriene inhibitor, and the optional decongestant, by
sequential administration of a terfenadine metabolite,
decongestant, and leukotriene inhibitor, by sequential
administration of leukotriene inhibitor, a terfenadine
metabolite, and decongestant, or in any other possible order,
such as decongestant followed by concurrent administration of
.a terfenadine metabolite and leukotriene inhibitor. The
-20 compositions administered in each of these methods may be
concurrent, sequential, or in any combination of concurrent
and/or sequential.
Adverse effects to be reduced or avoided by the
methods and compositions of the present invention include,
.25.but are not limited to: cardiotoxicity, such as cardiac
arrythmia or cardiac conduction disturbances; drowsiness;
nausea; fatigue; weakness; and headache.
Terfenadine metabolites and the isomers and salts
thereof, particularly fexofenadine and the isomers and salts
30 thereof, and other non-sedating antihistamines have
-antihistaminic activity and provide therapy and a reduction
of symptoms for a variety of conditions and disorders related
to allergic rhinitis and other allergic disorders, diabetes
mellitus, and other conditions; however, such drugs, while
-35 offering the expectation of efficacy, may cause adverse
effects. Utilizing a metabolite of terfenadine, preferably
fexofenadine, in combination with a leukotriene inhibitor,
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and optionally with a decongestant, results in clearer dose-
related definitions of efficacy, diminished adverse effects,
a superior therapy due to synergistic activity, and
accordingly, an improved therapeutic index. It is,
3 therefore, more desirable to use the compositions and methods
of the invention than to use terfenadine, or a metabolite
thereof, or a leukotriene inhibitor separately.
One of ordinary skill in the art is readily able to
synthesize fexofenadine or the other metabolites of
terfenadine, as well as their optically pure stereoisomers
and salts thereof, used in the compositions and methods of
the invention, such as by following the teachings of U.S.
Patent Nos. 4,254,129; 5,578,610; 5,581,011; 5,589,487; and
5,663,412.
The term "adverse effects" as used herein includes,
but is not limited to, cardiac arrhythmias, cardiac
conduction disturbances, appetite stimulation, weight gain,
sedation, gastrointestinal distress, headache, dry mouth,
3'0 constipation, and diarrhea. The term "cardiac arrhythmias"
includes, but is not limited to, ventricular
tachyarrhythmias, torsades de pointes, and ventricular
fibrillation.
The phrase "therapeutically effective amount" as
used herein means the amount of a terfenadine metabolite that
-provides a therapeutic benefit in the treatment, prevention,
or management of conditions that are responsive to histamine
antagonists, such as urticaria, allergic rhinitis,
inflammation, symptomatic dermographism, dermatitis, asthma,
allergic asthma, retinopathy or other small vessel disorders
associated with diabetes mellitus, and the symptoms
associated with asthma or allergic rhinitis such as
bronchoconstriction, cough, cold, cold-like, wheezing,
dyspnea, and/or flu symptoms including, but not limited to,
sneezing, rhinorrhea, lacrimation, and dermal irritation.
The phrase "therapeutically effective amount" as
used herein means the amount of leukotriene inhibitor that
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provides a therapeutic benefit In the treatment, prevention,
or management of conditions that are responsive to
leukotriene inhibitors, such as urticaria, allergic rhinitis,
symptomatic dermographism, dermatitis, asthma, inflammation,
retinopathy or other small vessel disorders associated with
diabetes mellitus, and the symptoms associated with asthma
and allergic rhinitis such as bronchoconstriction, cough,
cold, cold-like, wheezing, dyspnea, and/or flu symptoms
including, but not limited to, sneezing, rhinorrhea,
lacrimation, and dermal irritation.
The phrase "therapeutically effective amount" with
respect to decongestant as used herein means that amount of
decongestant alone, or in combination with other drugs, that
provides a therapeutic benefit in the treatment, prevention,
or management of any condition that is responsive to
decongestants, such as congestion of the respiratory tract
and/or the sinuses, and the symptoms associated with
congestion, such as cough, cold, cold-like, wheezing,
dyspnea, and/or flu symptoms including, but not limited to,
.20 sneezing, rhinorrhea, lacrimation, and dermal irritation.
The term "asthma" as used herein is defined as a
disorder characterized by increased responsiveness of the
trachea and bronchi to various stimuli, which results in
symptoms that include, but are not limited to, wheezing,
..25 cough, shortness of breath, bronchoconstriction, dyspnea, and
the like. Asthma includes, for example, allergic asthma.
The term "dermatitis" as used herein means that
disorder caused by inflammation to the skin including
endogenous and contact dermatitis such as, but not limited
30 to: actinic dermatitis (or photodermatitis), atopic
dermatitis, chemical dermatitis, cosmetic dermatitis,
dermatitis aestivalis, and seborrheic dermatitis.
The term "inflammation" as used herein is a
fundamental pathologic process of a dynamic complex of
35 cytologic and chemical reactions that occur in the affected
blood vessels and adjacent tissues in response to an injury
or abnormal stimulation caused by a physical, chemical, or
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.biologic agent, including: the local reactions and resulting
morphologic changes; the destruction or removal of the
injurious material; and the responses that lead to repair and
healing. The typical signs of inflammation are redness, heat
3 or warmth, swelling, pain, and occasionally inhibited or lost
function. All of the signs may be observed in certain
.instances, although any particular sign is not necessarily
always present.
The term "leukotriene inhibitor" as used herein
includes any agent or compound that inhibits, restrains,
retards or otherwise interacts with the action or activity of
leukotrienes, such as, but not limited to, 5-lipoxygenase
("5-LO") inhibitors, 5-lipoxygenase activating protein
("FLAP") antagonists, and leukotriene receptor antagonists
:15 ("LTRAs"), including leukotriene receptor antagonists
("LTRAs"). An exemplary LTRA is leukotriene D4 ("LTD,")
receptor antagonist.
The term "5-lipoxygenase inhibitor" or "5-LO
inhibitor" as used herein includes any agent or compound that
20.inhibits, restrains, retards or otherwise interacts with the
enzymatic action of 5-lipoxygenase, such as, but not limited
to, zileuton, docebenone, piripost, and ICI-D2318.
The term "S-lipoxygenase activating protein antagonist"
or "FLAP antagonist" as used herein includes any agent or
25-compound that inhibits, restrains, retards or otherwise
..interacts with the action or activity of 5-lipoxygenase
activating protein, such as, but not limited to, MK-591 and
MK-886.
The term "leukotriene receptor antagonist" or
3'0 ".LIRA" as used herein includes any agent or compound that
-inhibits, restrains, retards or otherwise antagonizes the
activity of receptors that are responsive to leukotrienes,
.including those responsive to leukotriene D,. Exemplary LTRAs
include, but are not limited to, sodium 1-(((R)-(3-(2-(6,7-
35 difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-
:propyl)phenyl)thio)methyl)cyclopropaneacetate; 1- (((1(R)-(3-
(2- (2, 3-dichlorothieno [3, 2-b] pyridin-5-yl) - (E) -
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ethenyl)phenyl)-3-(2-(1-hydroxy-_1-
methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid
or sodium or other salts thereof, pranlukast, zafirlukast
(ICI-204219), and montelukast (MK-476), the latter of which
_5 is sold commercially as SINGULAIR .
The magnitude of a prophylactic or therapeutic dose
of a terfenadine metabolite or leukotriene inhibitor in the
acute or chronic management of a disorder or condition will
vary with the severity of the condition to be treated and the
route of administration. The dose, and perhaps the dose
frequency, will also vary according to the age, body weight,
and response of the individual patient. Suitable total daily
dose ranges can be readily determined by those skilled in the
art. In general, the total daily dose range for a
terfenadine metabolite, for the conditions described herein,
is from about 0.01 mg to about 500 mg administered in single
or divided doses. For example, a preferred oral daily dose
range should be from about 1 mg to about 500 mg. A more
preferred oral dose is about 20 mg to about 200 mg. A
:20 preferred oral daily dose range of decongestant, such as
pseudoephedrine, should be from about 50 mg to about 300 mg,
more preferably, about 150 mg to about 250 mg. In addition,
suitable oral daily dosage ranges of leukotriene inhibitor
can be readily determined by those skilled in the art. For
.25 example, see the Physician's Desk Reference 1998 for
suitable dosages presently used for known leukotriene
inhibitors. For example, for 5-lipoxygenase inhibitors, the
oral daily dose range should be from about 20 mg to 2,500 mg,
preferably from about 20 mg to 800 mg. For leukotriene
.30 receptor antagonists, the oral daily dose range should be
from about 2 mg to 200 mg, preferably from about 5 mg to 20
mg. For 5-lipoxygenase activating protein antagonists, the oral
daily dose range should be from about 20 mg to about 2,500 mg.
it is further recommended that children, patients
aged over 65 years, and those with impaired renal or hepatic
.35 function initially receive low doses, and that they then be
titrated based on individual response(s) or blood level(s).
It may be necessary to use dosages outside these ranges in
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some cases as will be apparent to those skilled in the art.
Further, it is noted that the clinician or treating physician
will know how and when to adjust, interrupt, or terminate
therapy in conjunction with individual patient response.
The term "therapeutically effective amount of a
terfenadine metabolite or a pharmaceutically acceptable salt
thereof" is encompassed by the above-described dosage
amounts. In addition, the terms "said composition
comprising (i) a therapeutically effective amount of a
terfenadine metabolite or a pharmaceutically acceptable salt
thereof; and (ii) a therapeutically effective amount of a
leukotriene inhibitor" and "said composition comprising (i) a
therapeutically effective amount of a terfenadine metabolite
or a pharmaceutically acceptable salt thereof; (ii) a
therapeutically effective amount of a leukotriene inhibitor;
and (iii) a therapeutically effective amount of a
decongestant" are also encompassed by the above-described
dosage amounts and dose frequency schedule.
Any suitable route of administration may be
employed for providing the patient with an effective dosage
of a terfenadine metabolite and leukotriene inhibitor
according to the methods of the present invention. For
example, oral, intraoral, rectal, parenteral, epicutaneous,
transdermal, subcutaneous, intramuscular, intranasal,
sublingual, buccal, intradural, intraocular,
intrarespiratory, or nasal inhalation and like forms of
administration may be employed. Oral administration is
generally preferred. For the methods to treat dermatitis,
however, topical administration is preferred.
The pharmaceutical compositions used in the methods
of the present invention, which are sterile and stable,
include a terfenadine metabolite, the metabolic derivative of
terfenadine, or a pharmaceutically acceptable salt thereof, a
leukotriene inhibitor, and optionally a decongestant, as the
active ingredient. The compositions may also contain a
pharmaceutically acceptable carrier or excipient, and
optionally, other therapeutic ingredients.
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The term "pharmaceutically acceptable salt" refers
to a salt prepared from pharmaceutically acceptable non-toxic
acids or bases including inorganic acids or bases or organic
acids or bases. Examples of such inorganic acids are
.5 hydrochloric, hydrobromic, hydroiodic, sulfuric, and
phosphoric. Appropriate organic acids may be selected, for
example, from aliphatic,. aromatic, carboxylic and sulfonic
classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, glucuronic, maleic,
furoic, glutamic, benzoic, anthranilic, salicylic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethanesulfonic, pantothenic, benzenesulfonic, stearic,
sulfanilic, algenic, and galacturonic. Examples of such
inorganic bases include metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium, and zinc.
Appropriate organic bases may be selected, for example, from
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumaine (N-
methyiglucamine), lysine and procaine.
=20 The compositions for use in the methods of the
present invention can include suitable excipients or carriers
such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders,
disintegrating agents, and the like.
_25 Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, patches, gel caps, syrups,
elixirs, gels, powders, magmas, lozenges, ointments, creams,
pastes, plasters, lotions, discs, suppositories, nasal or
oral sprays, aerosols, and the like.
::30 Because of their ease of administration, tablets
and capsules represent the most advantageous oral dosage unit
form, in which case solid pharmaceutical carriers are
employed. If desired, tablets may be coated by standard
aqueous or nonaqueous techniques.
3.5 In addition to the common dosage forms set out
above, the compound for use in the methods of the present
invention may also be administered by controlled release
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means and/or delivery devices such as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and
4,008,719.
Pharmaceutical compositions for use in the methods
of the present invention may be prepared by any of the
methods of pharmacy, but all methods include the step of
bringing into association the active ingredient with the
carrier which constitutes one or more necessary ingredients.
In general, the compositions are prepared by uniformly and
intimately admixing the active ingredient with liquid
carriers or finely divided solid carriers or both, and then,
if necessary, shaping the product into the desired
presentation.
For example, a tablet may be prepared by
compression or molding, optionally, with one or more
accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a
free-flowing form such as powder or granules, optionally
mixed with a binder, lubricant, inert diluent, surface active
or dispersing agent. Molded tablets may be made by molding,
in a suitable machine, a mixture of the powdered compound
moistened with an inert liquid diluent.
The invention is further defined by reference to
the following example describing in detail the preparation of
the composition and the compositions used in the methods of
the present invention, as well as their utility. It will be
apparent to those skilled in the art that many modifications,
both to materials and methods, may be practiced which are
within the scope of this invention.
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.5. EXAMPLES
5.1. Example 1
A. Preparation of methyl R-4-[l-hydroxy-4-(4-
hydroxydiphenylmethyl-l-piperidinyl)butyl]-a,a-
dimethylbenzeneacetate
_5 4-(a-hydroxy-a-phenylbenzyl)piperidine (4.3 g) was
combined with methyl p-(4-chloro-1-oxobutyl)-a,a-
dimethylbenzeneacetate (4.5 g), potassium bicarbonate (2.9
g), potassium iodide (ca. 50 mg), and methyl isobutyl ketone
(50 mL) and heated to ref lux for 48 hrs. Additional 4-(a-
1.0 hydroxy-a-phenylbenzyl)piperidine (1.1 g) was added, and
heating was continued for an additional 48 hrs. Upon cooling
the mixture to room temperature, water was added and the pH
of the solution was adjusted to ca. 12 by addition of aqueous
sodium hydroxide. The mixture was extracted with ethyl
.i5 acetate. The ethyl acetate solution was washed with
saturated aqueous sodium bicarbonate and brine and dried over
sodium sulfate. The ethyl acetate was removed on a rotary
evaporator and the residue was treated with 25% ethyl acetate
in hexane. The resulting precipitate was filtered and air
.2.0 dried to give methyl 4-(1-oxo-4-(4-hydroxydiphenylmethyl-1-
piperidinyl)butyll-a,a-dimethylbenzeneacetate. This
intermediate precipitate (2.4 g) was combined with
tetrahydrofuran (10 mL) and (+) -f3-
chlorodiisopinocamphenylborane (4.5 g) and stirred for 48
hrs. Methanol (10 mL) and sodium bicarbonate (1.5 g) were
added to the reaction solution, and the mixture was stirred
for 12 hrs. The mixture was diluted with ethyl acetate (200
tnL) and washed with saturated aqueous sodium bicarbonate to
give methyl R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
'0.piperidinyl)butyl]-a,a-dimethylbenzeneacetate.
B. R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid
1R-(+)-terfenadine carboxylatel.
35 Methyl R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetate (1.2 g) was
combined with potassium hydroxide (0.4 g) and ethanol (5 mL),
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WO 99/52554 PCT/US99/08077
and the mixture was heated to reflux for 7 hours. The
ethanol was removed on a rotary evaporator and the residue
was dissolved in water (2 mL). The aqueous solution was
acidified with glacial acetic acid to provide a solid which
was recrystallized two times from 1:1 methanol/ethyl acetate
to give R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid (R-
terfenadine carboxylate) (mp=213-215 C).
C. Preparation of methyl S-4-(1-hydroxy-4-(4-
hydroxydiphenylmethyl-i-piperidinyl)butyl)-a,a-
dimethylbenzeneacetate.
4-(a-hydroxy-a-phenylbenzyl)piperidine (4.3 g) was
combined with methyl p-(4-chloro-l-oxobutyl)-a,a-dimethyl-
benzene-acetate (4.5 g), potassium bicarbonate (2.9 g),
potassium iodide (ca. 50 mg), and methyl isobutyl ketone (50
mL) and heated to reflux for 48 hours. Additional 4-(a-
hydroxy-a-phenylbenzyl)piperidine (1.1 g) was added, and
heating was continued for an additional 48 hours. Upon
cooling the mixture to room temperature, water was added and
-20 the pH of the solution was adjusted to ca. 12 by addition of
aqueous sodium hydroxide. The mixture was extracted with
ethyl acetate. The ethyl acetate solution was washed with
saturated aqueous sodium bicarbonate and brine and dried over
sodium sulfate. The ethyl acetate was removed on a rotary
.25 evaporator and the residue was treated with 25% ethyl acetate
in hexane. The resulting precipitate was filtered and air
dried to give methyl 4-[1-oxo-4-(4-hydroxydiphenyl-methyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetate. This
intermediate precipitate (2.4 g) was combined with
30 tetrahydrofuran (10 mL) and (-)-B-
chlorodiisopinocamphenylborane (4.5 g) and stirred for 48
hours. Methanol (10 mL) and sodium bicarbonate (1.5 g) were
added to the reaction solution and the mixture was stirred
for 12 hours. The mixture was diluted with ethyl acetate
35 (200 mL) and washed with saturated aqueous sodium bicarbonate
to give methyl S-4-[l-hydroxy-4-(4-hydroxydiphenylmethyl-l-
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CA 02328074 2007-08-14
piperidinyl)butyl]-a,a-dimethylbenzeneacetate. If the
aforementioned intermediate precipitate was to be reacted
with racemic 1-chlorodiisopinocamphenylborane, then a racemic
mixture of methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetate would be
produced.
D. S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid
(S-(-)-terfenadine carboxylatel.
Methyl S-4-[l-hydroxy-4-(4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetate (1.2 g) was
combined with potassium hydroxide (0.4 g) and ethanol (5 mL)
and the mixture was heated to reflux for 7 hours. The
ethanol was removed on a rotary evaporator and the residue
was dissolved in water (2 mL). The aqueous solution was
acidified with glacial acetic acid to provide a solid which
was recrystallized two times from 1:1 methanol/ethyl acetate
to give S- (-) -4- [1-hydr-oxy-4- (4-hydroxydiphenylmethyl-l-
piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid [(S)-
terfenadine carboxylate] (mp=215-218 C).
Various modifications of the invention in addition
to those shown and described herein will be apparent to those
skilled in the art from the foregoing description. Such
modifications are also intended to fall within the scope of
the appended claims.
The above disclosure includes all the information
deemed essential to enable those skilled in the art to
practice the claimed invention.
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